The Function of BTG3 in Colorectal Cancer Cells and Its Possible Signaling Pathway

Overview

Journal J Cancer Res Clin Oncol

Specialty Oncology

Date 2017 Dec 23

PMID 29270670

Citations 14

Authors

Chi Lv

Heling Wang

Yuxin Tong

Hongzhuan Yin

Dalu Wang

Zhaopeng Yan

Yichao Liang

Di Wu

Qi Su

Affiliations

Soon will be listed here.

Abstract

Purpose: B-cell translocation gene 3 (BTG3) has been identified as a candidate driver gene for various cancers, but its specific role in colorectal cancer (CRC) is poorly understood. We aimed to investigate the relationship between expression of BTG3 and clinicopathological features and prognosis, as well as to explore the effects and the role of a possible BTG3 molecular mechanism on aggressive colorectal cancer behavior.

Methods: BTG3 expression was assessed by immunohistochemistry (IHC) on specimens from 140 patients with CRC. The association of BTG3 expression with clinicopathological features was examined. To confirm the biological role of BTG3 in CRC, two CRC cell lines expressing BTG3 were used and BTG3 expression was knocked down by shRNA. CCK-8, cell cycle, apoptosis, migration, and invasion assays were performed. The influence of BTG3 knockdown was further investigated by genomic microarray to uncover the potential molecular mechanisms underlying BTG3-mediated CRC development and progression.

Results: BTG3 was downregulated in colorectal cancer tissues and positively correlated with pathological classification (p = 0.037), depth of invasion (p = 0.016), distant metastasis (p = 0.024), TNM stage (p = 0.007), and overall survival (OS) and disease-free survival (DFS). BTG3 knockdown promoted cell proliferation, migration, invasion, relieved G2 arrest, and inhibited apoptosis in HCT116 and LoVo cells. A genomic microarray analysis showed that numerous tumor-associated signaling pathways and oncogenes were altered by BTG3 knockdown. At the mRNA level, nine genes referred to the extracellular-regulated kinase/mitogen-activated protein kinase pathway were differentially expressed. Western blotting revealed that BTG3 knockdown upregulated PAK2, RPS6KA5, YWHAB, and signal transducer and activator of transcription (STAT)3 protein levels, but downregulated RAP1A, DUSP6, and STAT1 protein expression, which was consistent with the genomic microarray data.

Conclusions: BTG3 expression might contribute to CRC carcinogenesis. BTG3 knockdown might strengthen the aggressive colorectal cancer behavior.

Citing Articles

DUSP6 regulates Notch1 signalling in colorectal cancer.

Png C, Weerasooriya M, Li H, Hou X, Teo F, Huang S Nat Commun. 2024; 15(1):10087.

PMID: 39572549 PMC: 11582695. DOI: 10.1038/s41467-024-54383-y.

TRIM65 promotes renal cell carcinoma through ubiquitination and degradation of BTG3.

Zhang Q, Li Y, Zhu Q, Xie T, Xiao Y, Zhang F Cell Death Dis. 2024; 15(5):355.

PMID: 38777825 PMC: 11111765. DOI: 10.1038/s41419-024-06741-3.

A pan-cancer analysis of anti-proliferative protein family genes for therapeutic targets in cancer.

Zhang S, Gu J, Shi L, Qian B, Diao X, Jiang X Sci Rep. 2023; 13(1):21607.

PMID: 38062199 PMC: 10703880. DOI: 10.1038/s41598-023-48961-1.

The clinicopathological significances and related signal pathways of BTG3 mRNA expression in cancers: A bioinformatics analysis.

Zheng H, Xue H, Zhang C, Shi K, Zhang R Front Genet. 2022; 13:1006582.

PMID: 36186486 PMC: 9523479. DOI: 10.3389/fgene.2022.1006582.

Long non-coding RNA cancer susceptibility candidate 2 regulates the function of human fibroblast-like synoviocytes via the microRNA-18a-5p/B-cell translocation gene 3 signaling axis in rheumatoid arthritis.

Ye Z, Wei L, Yin X, Li H, Qin G, Li S Bioengineered. 2022; 13(2):3240-3250.

PMID: 35045800 PMC: 8974001. DOI: 10.1080/21655979.2021.2022075.

References

Siegel R, DeSantis C, Jemal A . Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014; 64(2):104-17. DOI: 10.3322/caac.21220. View

Tkach M, Rosemblit C, Rivas M, Proietti C, Diaz Flaque M, Mercogliano M . p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth. Endocr Relat Cancer. 2013; 20(2):197-212. DOI: 10.1530/ERC-12-0194. View

Hurd T, Culbert A, Webster K, Tavare J . Dual role for mitogen-activated protein kinase (Erk) in insulin-dependent regulation of Fra-1 (fos-related antigen-1) transcription and phosphorylation. Biochem J. 2002; 368(Pt 2):573-80. PMC: 1223008. DOI: 10.1042/BJ20020579. View

Balmanno K, Chell S, Gillings A, Hayat S, Cook S . Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer. 2009; 125(10):2332-41. DOI: 10.1002/ijc.24604. View

Wu Y, Jan Y, Ko B, Liang S, Liou J . Involvement of 14-3-3 Proteins in Regulating Tumor Progression of Hepatocellular Carcinoma. Cancers (Basel). 2015; 7(2):1022-36. PMC: 4491697. DOI: 10.3390/cancers7020822. View

Yuan Z, Guan Y, Wang L, Wei W, Kane A, Chin Y . Central role of the threonine residue within the p+1 loop of receptor tyrosine kinase in STAT3 constitutive phosphorylation in metastatic cancer cells. Mol Cell Biol. 2004; 24(21):9390-400. PMC: 522220. DOI: 10.1128/MCB.24.21.9390-9400.2004. View

Karpinski B, Morle G, Huggenvik J, Uhler M, Leiden J . Molecular cloning of human CREB-2: an ATF/CREB transcription factor that can negatively regulate transcription from the cAMP response element. Proc Natl Acad Sci U S A. 1992; 89(11):4820-4. PMC: 49179. DOI: 10.1073/pnas.89.11.4820. View

Zeng Q, Li S, Chepeha D, Giordano T, Li J, Zhang H . Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005; 8(1):13-23. DOI: 10.1016/j.ccr.2005.06.004. View

Alejandro E, Johnson J . Inhibition of Raf-1 alters multiple downstream pathways to induce pancreatic beta-cell apoptosis. J Biol Chem. 2007; 283(4):2407-17. PMC: 3025401. DOI: 10.1074/jbc.M703612200. View

10.

Han L, Colicelli J . A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1. Mol Cell Biol. 1995; 15(3):1318-23. PMC: 230355. DOI: 10.1128/MCB.15.3.1318. View

11.

Lv Z, Zou H, Peng K, Wang J, Ding Y, Li Y . The suppressive role and aberrent promoter methylation of BTG3 in the progression of hepatocellular carcinoma. PLoS One. 2013; 8(10):e77473. PMC: 3798399. DOI: 10.1371/journal.pone.0077473. View

12.

Davie J, Spencer V . Signal transduction pathways and the modification of chromatin structure. Prog Nucleic Acid Res Mol Biol. 2000; 65:299-340. DOI: 10.1016/s0079-6603(00)65008-0. View

13.

Sofroniew M, Howe C, Mobley W . Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci. 2001; 24:1217-81. DOI: 10.1146/annurev.neuro.24.1.1217. View

14.

Healy S, Khan P, He S, Davie J . Histone H3 phosphorylation, immediate-early gene expression, and the nucleosomal response: a historical perspective. Biochem Cell Biol. 2012; 90(1):39-54. DOI: 10.1139/o11-092. View

15.

Ahmed D, Eide P, Eilertsen I, Danielsen S, Eknaes M, Hektoen M . Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis. 2013; 2:e71. PMC: 3816225. DOI: 10.1038/oncsis.2013.35. View

16.

Cassidy S, Syed B . Colorectal cancer drugs market. Nat Rev Drug Discov. 2017; 16(8):525-526. DOI: 10.1038/nrd.2017.59. View

17.

Weng C, Chau C, Hsieh Y, Yang S, Yen G . Lucidenic acid inhibits PMA-induced invasion of human hepatoma cells through inactivating MAPK/ERK signal transduction pathway and reducing binding activities of NF-kappaB and AP-1. Carcinogenesis. 2007; 29(1):147-56. DOI: 10.1093/carcin/bgm261. View

18.

Chen X, Chen G, Cao X, Zhou Y, Yang T, Wei S . Downregulation of BTG3 in non-small cell lung cancer. Biochem Biophys Res Commun. 2013; 437(1):173-8. DOI: 10.1016/j.bbrc.2013.06.062. View

19.

Wolfgang C . Role of fourth-generation troponin in predicting mortality in noncardiac surgery. JAMA Surg. 2013; 148(1):12-3. DOI: 10.1001/jamasurg.2013.607. View

20.

Lai K, Huang A, Hsu S, Kuo C, Yang J, Wu S . Benzyl isothiocyanate (BITC) inhibits migration and invasion of human colon cancer HT29 cells by inhibiting matrix metalloproteinase-2/-9 and urokinase plasminogen (uPA) through PKC and MAPK signaling pathway. J Agric Food Chem. 2010; 58(5):2935-42. DOI: 10.1021/jf9036694. View